The proteoglycan 4 (prg4) gene encodes for highly glycosylated proteins termed megakaryocyte stimulating factor (MSF), lubricin, and superficial zone protein (SZP) (1). These molecules are collectively referred to as PRG4 or PRG4 proteins. PRG4 is present in synovial fluid and at the surface of synovium (2), tendon (3), and meniscus (4) and is suspected as being an important component for healthy synovial joints. See, e.g., (5), (6).
In tissues such as synovial joints, physicochemical modes of lubrication have been classified as fluid film or boundary. The operative lubrication modes depend on the normal and tangential forces on the articulating tissues, on the relative rate of tangential motion between these surfaces, and on the time history of both loading and motion. The friction coefficient, μ, provides a quantitative measure, and is defined as the ratio of tangential friction force to the normal force. One type of fluid-mediated lubrication mode is hydrostatic. At the onset of loading and typically for a prolonged duration, the interstitial fluid within cartilage becomes pressurized, due to the biphasic nature of the tissue; fluid may also be forced into the asperities between articular surfaces through a weeping mechanism. Pressurized interstitial fluid and trapped lubricant pools may therefore contribute significantly to the bearing of normal load with little resistance to shear force, facilitating a very low μ. Also, at the onset of loading and/or motion, squeeze film, hydrodynamic, and elastohydrodynamic types of fluid film lubrication occur, with pressurization, motion, and deformation acting to drive viscous lubricant from and/or through the gap between two surfaces in relative motion.
The relevant extent to which fluid pressure/film versus boundary lubrication occurs classically depends on a number of factors (13). When lubricant film can flow between the conforming sliding surfaces, which can deform elastically, elastohydrodynamic lubrication occurs. Pressure, surface roughness, and relative sliding velocity determine when full fluid lubrication begins to break down and the lubrication enters new regimes. As velocity decreases further, lubricant films adherent to the articulating surfaces begin to contribute and a mixed regime of lubrication occurs. If the velocity decreases even further and only an ultra-thin lubricant layer composed of a few molecules remain, boundary lubrication occurs. A boundary mode of lubrication is therefore indicated by a friction coefficient (ratio of the measured frictional force between two contacting surfaces in relative motion to the applied normal force) during steady sliding being invariant with factors that influence formation of a fluid film, such as relative sliding velocity and axial load (14). For articular cartilage, it has been concluded boundary lubrication is certain to occur, although complemented by fluid pressurization and other mechanisms (15-18).
In boundary lubrication, load is supported by surface-to-surface contact, and the associated frictional properties are determined by lubricant surface molecules. This mode has been proposed to be important because the opposing cartilage layers make contact over ˜10% of the total area, and this may be where most of the friction occurs (19). Furthermore, with increasing loading time and dissipation of hydrostatic pressure, lubricant-coated surfaces bear an increasingly higher portion of the load relative to pressurized fluid, and consequently, this mode can become increasingly dominant (13, 20). Boundary lubrication, in essence, mitigates stick-slip (13), and is therefore manifest as decreased resistance both to steady motion and the start-up of motion. The latter situation is relevant to load bearing articulating surfaces after prolonged compressive loading (e.g., sitting or standing in vivo) (21). Typical wear patterns of cartilage surfaces (22) also suggest that boundary lubrication of articular cartilage is critical to the protection and maintenance of the articular surface structure.
With increasing loading time and dissipation of hydrostatic pressure, lubricant-coated surfaces bear an increasingly higher portion of the load relative to pressurized fluid, and consequently, μ can become increasingly dominated by this mode of lubrication. A boundary mode of lubrication is indicated by values of μ during steady sliding being invariant with factors that influence formation of a fluid film, such as relative sliding velocity and axial load. Boundary lubrication, in essence, mitigates stickslip, and is therefore manifest as decreased resistance both to steady motion and the start-up of motion.
The precise mechanisms of boundary lubrication at biological interfaces are currently unknown. However, proteoglycan 4 (PRG4) may play a critical role as a boundary lubricant in articulating joints. This secreted glycoprotein is thought to protect cartilaginous surfaces against frictional forces, cell adhesion and protein deposition. Various native and recombinant lubricin proteins and isoforms have been isolated and characterized. For instance, U.S. Pat. Nos. 5,326,558; 6,433,142; 7,030223, and 7,361,738 disclose a family of human megakaryocyte stimulating factors (MSFs) and pharmaceutical compositions containing one or more such MSFs for treating disease states or disorders, such as a deficiency of platelets. U.S. Pat. Nos. 6,960,562 and 6,743,774 also disclose a lubricating polypeptide, tribonectin, comprising a substantially pure fragments of MSF, and methods of lubricating joints or other tissues by administering tribonectin systemically or directly to tissues.
A challenge to boundary lubrication is the presence of inflammation in surrounding tissues, as well as increased protease levels in the synovial fluid. Loss of the boundary-lubricating ability of synovial fluid after injury is associated with damage to the articular cartilage matrix. This can be attributed to inflammatory processes resulting from the injury, particularly in the early phases. Another challenge to boundary lubrication is a sex steroid imbalance, especially in arthritic disorders such as rheumatoid arthritis. Sex steroids are involved in the pathogenesis and regulation of inflammation in rheumatoid arthritis, a disease characterized by chronic inflammatory synovitis. Androgens suppress, whereas estrogens promote, inflammatory processes. Consequently, the relative levels of androgens and estrogens in the synovial environment are extremely important in determining the progression of inflammation (7, 8, 23). Various androgen compounds reduce the magnitude of lymphocyte infiltration in lacrimal tissue. See, e.g., U.S. Pat. Nos. 5,620,921; 5,688,765; 5,620,921; and 6,107,289.
Engineering of contact lens surfaces have traditionally focused on increasing oxygen transport. Recent advances in contact lens chemistries have also focused on increasing water content and hydrophilicity to inhibit protein deposition on the lens surface. Protein deposition on the posterior/inner surface of the contact lens surfaces has been implicated as a causative factor in the corneal abrasions and mechanical trauma associated with contact lens wear.
Advances in silicone hydrogel materials have gained popularity due to their ability to reduce protein absorption through increased hydrophilicity. Examples include Lotrafilcon A (N,N-dimethylacrylamide, trimethylsiloxy silane and siloxane monomer, CIBA Vision, a.k.a. Focus NIGHT & DAY, 24% water content, 175 Dk/t O2 transmissibility), Lotrafilcon B (N,N-dimethylacrylamide, trimethylsiloxy silane and siloxane monomer, CIBA Vision, a.k.a. O2 Optix, 33% water content, 138 Dk/t O2 transmissibility), Balafilcon (N-vinyl pyrrolidone, tris-(trimethylsiloxysilyl)propylvinyl carbamate, N-carboxyvinyl ester, poly(dimethysiloxy)di(silylbutanol)bis(vinyl carbamate), Bausch & Lomb, a.k.a. PureVision, 36% water content, 101 Dk/t O2 transmissibility), Galyfilcon A (monofunctional polydimethylsiloxane, N,N-dimethylacrylamide, poly-2-hydroxyethyl methacrylate, siloxane monomer, polyvinyl pyrrolidone, ethyleneglycol dimethacrylate, Johnson & Johnson Vision Care, a.k.a. ACUVUE Advance, 47% water content, 86 Dk/t O2 transmissibility), Etafilcon AA (poly-2-hydroxyethyl methacrylate, methacrylic acid, Johnson & Johnson Vision Care, a.k.a. ACUVUE 2, 58% water content, 21 Dk/t O2 transmissibility). In addition to the material choices, these silicone hydrogel lenses are also manufactured with an additional treatment steps to improve hydrophilicity. For example, Lotrafilcon A & B use plasma coating, Balafilcon A makes use of a plasma oxidation process, and ACUVUE Advance lenses include polyvinyl pyrrolidone as an internal wetting agent [25]. Plasma treatments are known to fade and lose efficacy over time.
Protein adsorption at contact lens surfaces is commonly attributed to human albumin and lysozyme, two of the most abundant proteins in the tear film. Conflicting results have been reported regarding the water content, hydrophobicity, charge, pore size and surface roughness. Because the isoelectric points of albumin and lysozyme are on opposite ends of the pH of human tear, the minimum protein adsorption seems to occur when charge, water content and hydrophilicity are properly balanced. Lower water content materials tend to bind albumin while higher water content materials tend to bind lysozyme [24]. Luensmann et. al. [24] also indicated that silicone hydrogels exhibit both hydrophobic and hydrophilic domains; and following evaporation, chain rotation forces tend to expose hydrophobic domains to the air, thereby increasing the chance for dry spots. Polar lipids may also bind to hydrophilic regions on the lens surface, resulting in exposed hydrophobic tails, which may also promote dry spots.
Hyperosmolarity is a common result of contact lens wear. Those with a reduced quantity or quality of lipid production tend to exhibit drastically less stable tear films, and the presence of a contact lens may exacerbate the instability. This leads to a faster evaporation of the tear film, and a concentration of the tears over the ocular surface.